PROJECT SUMMARY Intracerebral hemorrhage (ICH) is the most morbid form of stroke and has no treatment approved by the US Food and Drug Administration. Hematoma expansion (HE), interval growth of the hematoma, is a proximate cause of worse patient outcomes and death as larger hematomas displace brain tissue; hematomas > 60 mL reliably lead to disability or death at follow-up. Preventing HE is a promising strategy to improve outcomes for patients with ICH. Our relative inability to predict HE, however, has impeded the development of effective treatment strategies for ICH, and several clinical trials have been unsuccessful. Even when HE has been reduced, our ability to detect a benefit is hampered by relatively insensitive patient outcomes. This proposal will resolve two roadblocks that prevent the development of effective treatments for ICH, the most morbid form of stroke. Three comprehensive stroke centers (two from the Northwestern Medicine system in metropolitan Chicago, IL, and the University of Texas at Houston) will partner to prospectively enroll patients with ICH, measure hemostasis, measure HE, and record patient outcomes with state of the art assessments, including the NIH Patient Reported Outcomes Measurement Information System (PROMIS) and NIH Toolbox. First, we will determine the mechanisms that lead to HE in acute ICH, broadly grouped into platelet activity, activation of coagulation, and fibrinolysis. Each can be specifically measured and has specific treatments to improve it. For example, reduced platelet activity due to aspirin can be reliably improved with desmopressin, delayed activation of coagulation may be related to hypomagnesemia, and accelerated fibrinolysis may be reduced with tranexamic acid or aminocaproic acid. Each will be examined for predicting HE; if multiple pathways are found, we will determine which are most important with machine learning. Once the most important mechanisms of hemostasis for HE are determined, we will explore if specific therapies improve platelet activity. It is possible that specific treatments for specific deficits in hemostasis will be more likely to reduce HE than single therapies applied to ICH patients generally (e.g., Factor VII). Once hemostatic mechanisms of HE are determine, we will determine the effect of HE on patient outcomes such as the modified Rankin Scale (mRS, a global ordinal scale), PROMIS, and NIH Toolbox. This will be crucial to plan for future clinical trials intended to improve patient outcomes through correcting abnormal hemostasis in acute ICH. Results will apply broadly to other bleeding conditions (e.g., neurotrauma).